This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Human immunodeficiency virus (HIV-1, HIV-2) and simian immunodeficiency virus (SIV) negative factor (Nef) is a 27-34 kDa viral accessory protein expressed in abundance early in the viral replicative cycle. Dispensable during viral replication, Nef plays an important role in increasing the pathogenicity and virulence of an HIV infection in part by modulation of T-cell activity, presumably through its demonstrated interaction with the zeta signaling chain of the T-cell receptor (TCRzeta). At present, we have crystallized a complex containing the core domain of SIV Nef and a fragment of the TCRzeta and obtained diffraction data up to 6-8A at our home source. Access to a more powerful beamline will result in higher resolution data that should allow for determination of a high resolution structure of the complex. Structural details of the Nef-TCRzeta complex will reveal not only the interaction sites on each protein but also provide insight into how Nef induces immunomodulatory activity through the TCR.